Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction

RESEARCH ARTICLE Assessment of Olfactory Function in MAPTAssociated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction a11111 OPEN ACCESS Citation: Markopoulou K, Chase BA, Robowski P, Strongosky A, Narożańska E, Sitek EJ, et al. (2016) Assessment of Olfactory Function in MAPTAssociated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a NonDisease-Specific, General Characteristic of Olfactory Dysfunction. PLoS ONE 11(11): e0165112. doi:10.1371/journal.pone.0165112 Editor: Mathias Toft, Oslo Universitetssykehus, NORWAY Received: June 4, 2016 Accepted: October 6, 2016 Published: November 17, 2016 Copyright: © 2016 Markopoulou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All data underlying the findings presented in this manuscript are available as supporting information (S1 File), with the exception of information that would allow identification of NMCs and control subjects, and individual members of the EPIPARK cohort, which has been withheld to maintain their confidentiality. These confidential data are available by contacting the corresponding author (KM) at , and will be Katerina Markopoulou1☯*, Bruce A. Chase2☯, Piotr Robowski3,4, Audrey Strongosky5, Ewa Narożańska3,4, Emilia J. Sitek3,4, Mariusz Berdynski6, Maria Barcikowska6, Matt C. Baker5, Rosa Rademakers5, Jarosław Sławek3,4, Christine Klein7, Katja Hückelheim7,8, Meike Kasten7,8, Zbigniew K. Wszolek9 1 NorthShore University Health System, Evanston, Illinois, United States of America, 2 Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, United States of America, 3 Department of Neurological and Psychiatric Nursing, Medical University of Gdańsk, Gdańsk, Poland, 4 Department of Neurology, St. Adalbert Hospital, Copernicus PL Sp. z o.o, Gdańsk, Poland, 5 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America, 6 Department of Neurodegenerative Disorders, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland, 7 Institute of Neurogenetics, University of Lübeck, Lübeck, Germany, 8 Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany, 9 Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America ☯ These authors contributed equally to this work. * Abstract Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson’s disease, Lewy body disease and Alzheimer’s disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, PLOS ONE | DOI:10.1371/journal.pone.0165112 November 17, 2016 1 / 23 Odor-Identification Irreproducibility in MAPT Disease released to researchers who meet the criteria for access to confidential data subject to approval of the Mayo Clinic Institutional Review Boards, the Bioethics Committee of the Medical University of Gdańsk, and/or the Ethikkommision der Universität zu Lübeck. Funding: KM, PR, AS, EN, EJS, MBer, MBar, MCB, JS and KH report no disclosure. ZKW is funded by the NIH (NS057567, P50 NS072187; http://www. ninds.nih.gov), the Mayo Clinic Center for Regenerative Medicine and Center for Individualized Medicine, the Mayo Clinic Neuroscience Focused Research Team Grant, and a gift from Carl Edward Bolch Jr. and Susan Bass Bolch. CK is funded by the German Research Foundation (KL 1134/11-1; KL 1134/12-1; KL 1134/13-1, SFB 936; SFB 134; www.dfg.de/en/ research_funding/programmes/index.jsp), the German Federal Ministry of Education and Research (BMBF) (01ED1406; www.bmbf.de), and StemBANCC (15439-2; stembancc.org) and is the recipient of a career development award from the Hermann and Lilly Schilling Foundation (www. schilling-stiftung.de). MK is funded by the German Research Foundation (KA 3179/2-1). RR is funded by the NIH (R01 NS080882, R01 NS065782, R01 AG026251, R01 NS076471, and P50 AG16574), the ALS Therapy Alliance (alstherapyalliance.org), and the Consortium for Frontotemporal Degeneration Research (http://memory.ucsf.edu/ ftd/research/laboratory/cfr). BAC is funded by the FIRE and UCRCA programs at the University of Nebraska at Omaha (http://www.unomaha.edu/ office-of-research-and-creative-activity). Individuals employed or contracted by the funders, other than the named authors, played no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript. Competing Interests: PR, AS, EN, EJS, MBer, MBar, and MCB declare that no competing interests exist. RR received received honoraria for lectures or educational activities not funded by industry; she serves on the medical advisory board of the Association for Frontotemporal Degeneration, on the board of directors of the International Society for Frontotemporal Dementia and holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. ZKW serves as Co-Editor-in-Chief of Parkinsonism and Related Disorders, Associate Editor of the European Journal of Neurology, and on the editorial boards of Neurologia i Neurochirurgia Polska, Advances in Rehabilitation, the Medical Journal of the Rzeszow University, and Clinical and Experimental Medical Letters; holds when 78 individuals without neurodegenerative disease an (...truncated)